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Agonists which cause irreversible covalent bonding

Nagelfar

Nagelfar

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There's Oxymorphazone, which bonds irreversibly to the μ-opioid receptor as an agonist. Are there any others? Ones which for example bond to sigma receptors or to dopamine transporters, irreversibly as agonists?
 
Covalent binding is a highly unfavored reaction for a pharmaceutical compound, which is just supposed to (de)activate a certain receptor. The only way of deactivating it would be complete internalisation (and digestion) of the receptor.

I doubt there are many more examples out there. Those compounds were developed just for research-purposes, to activate a receptor irreversibly...
 
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An irreversible agonist for adreno-receptors, in particular alpha1B, D, C and alpha2A/D-subtypes is chloroethylclonidine.
Ref: General Pharmacology 1997, 28(2), p.197

alpha-chlornaltrexamine is a µ-agonist with covalent binding capacities, too, being somehow 22times more potent than morphine. The alkylating group is a bis(chloroalkyl)amino-residue.
Ref: Journal of Medicinal Chemistry 1983, 26(4), p.503

N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) is an irreversible dopamine-receptor antagonist and not very selective to my knowledge.
Ref: Neuroscience Letters 1992, 137(2), p.265

(-)-N-(2-chloroethyl)-norapomorphine was thought to be a irreversible agonist but proved to be reversible.
Ref: European Journal of Pharmacology 1982, 77(1), p.85

Azapride, i.e., 4-azido-5-chloro-2-methoxy-N-[1-(phenylmethyl)-4-piperidinyl]benzamide, the azide derivative of the dopamine antagonist clebopride, is a irreversible dopamine-agonist.
Ref: European Journal of Biochemistry 1984, 145(2), p.273

Some nasty organic isocyanates were also published for the purpose of 'permanent' binding, but they are really far-out...Toxic stuff like hell.

Peace! Murphy
 
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One last more, bromocriptine...

The ability of the dopamine receptor antagonist spiperone [749-02-0] to block dopamine [51-61-6]- or bromocriptine (I) [25614-03-3]- inhibited prolactin [9002-62-4] release from dispersed rat anterior pituitary cells was tested in vitro. In a continuously perfused cell column app., spiperone rapidly counteracted the inhibitory effect of dopamine but was unable to reverse the inhibitory effect of I when added 30 min after I. However, spiperone completely blocked the action of I if added simultaneously with I. These basic data were confirmed, and the time relations more accurately defined, in static incubations of monolayer culture. Spiperone blocked the typical inhibition of prolactin release by I only if the cells were pre- or coincubated with the antagonist. If spiperone was added as soon as 1 min after I, the antagonist was unable to block the complete expression of the I inhibition. Evidently, I is a functionally irreversible dopamine agonist for at least the 4 h of these studies.
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But please note, that they say nothing (!) about covalent binding and speak strictly about functional agonism. That's slightly different from what you asked, but it fits the topic anyway...

Ah yeah, the source: European Journal of Pharmacology 1984, 99(1), p.85

Cheers! Murphy
 
Thank you. I'm so obsessive compulsive I had to start each of those as Wikipedia articles with the information you gave seeing only the last one actually had an article. hah.
 
MurphyClox said:
An irreversible agonist for adreno-receptors, in particular alpha1B, D, C and alpha2A/D-subtypes is chloroethylclonidine.
Ref: General Pharmacology 1997, 28(2), p.197
Peace! Murphy
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Okay so I am quite the newb when it comes to neurochemistry but I am still learning things. So in theory if someone took this drug, would their Mu receptor be constantly activated? Would they feel an opiate high 100% of the time?
 
The one that you cited, chloroethylclonidine, would activate the ADRENO-receptor, in particular the mentioned subtypes.

But the compound from the starting post, oxymorphazone, would be a µ-activator. A 'constant' one, correct! But this 'constant' counts only as long until the receptor gets deactivated by means of internalisation (that is re-uptake into the cell). The time span would be several hours, I think.

Such compounds serve only research-purposes (e.g. labeling of receptors) and I would never recommend them to be swallowed by humans. The effects could be disastrous! (fatality at extreme low doses possible!)

Murphy
 
MurphyClox said:
But the compound from the starting post, oxymorphazone, would be a µ-activator. A 'constant' one, correct! But this 'constant' counts only as long until the receptor gets deactivated by means of internalisation (that is re-uptake into the cell). The time span would be several hours, I think.
Click to expand...

I believe the article on oxymorphazone at Wikipedia said a full 48 hours I'm assuming on average, so that's quite a bit longer than your usual opioid effect.
 
Limpet_Chicken said:
Isoguavacine-N-oxide is an irreversible alkylating agonist for the GABA binding site at GABAa.
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Thanks. Is that 'Isoguavacine' or 'Isoguvacine' and what's your source? I'm always acutely aware at how much chemical information there is out there not yet readily findable online.
 
Ok so if an agonist forms a covalent bond with a receptor the cell comes and gobbles up the receptor? That's sick man.
 
Sounds like a recipe for disaster -- if you destroy the receptor binding sites you're basically administering a neurotoxin.
 
Right, but it doesn't take all that long for a new receptor protein to express itself.
 
Yeah, these compounds are all quite potent, because once attachted to the target, they won't dissociate away. Therefore, the initial affinity doesn't have to be this high.
The necessity of complete re-synthesis of the receptors (which costs time and energy in a neuron!) adds indeed some 'nice' long-term action, or call it 'toxicity' if you like to.

As said before, these are all research-only compounds, in no way intented to be taken by humans to my best knowledge. You will also find not much examples at all, where a pharmaceutical compound covalently (de)activates a process. Exceptions are known but not the rule!

Murphy
 
MurphyClox said:
An irreversible agonist for adreno-receptors, in particular alpha1B, D, C and alpha2A/D-subtypes is chloroethylclonidine.
Ref: General Pharmacology 1997, 28(2), p.197

alpha-chlornaltrexamine is a µ-agonist with covalent binding capacities, too, being somehow 22times more potent than morphine. The alkylating group is a bis(chloroalkyl)amino-residue.
Ref: Journal of Medicinal Chemistry 1983, 26(4), p.503

N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) is an irreversible dopamine-receptor antagonist and not very selective to my knowledge.
Ref: Neuroscience Letters 1992, 137(2), p.265

(-)-N-(2-chloroethyl)-norapomorphine was thought to be a irreversible agonist but proved to be reversible.
Ref: European Journal of Pharmacology 1982, 77(1), p.85

Azapride, i.e., 4-azido-5-chloro-2-methoxy-N-[1-(phenylmethyl)-4-piperidinyl]benzamide, the azide derivative of the dopamine antagonist clebopride, is a irreversible dopamine-agonist.
Ref: European Journal of Biochemistry 1984, 145(2), p.273

Some nasty organic isocyanates were also published for the purpose of 'permanent' binding, but they are really far-out...Toxic stuff like hell.

Peace! Murphy
Click to expand...

I love it how no one ever even has to ask for proof with you mate :)
 
_OFFTOPIC ON:
It is my honest intention, always to proof what I'm stating.
Either by citing own experience (the worst proof; too subjective and sample size = 1), or by citing textbooks and scientific journals.

That's also the reason why I almost never posted outside ADD here at Bluelight. The discussions are led astray after a couple of posts, and people keep on stating absolute bullshit, until a mod chimes in and brings the thread back on topic and 'back to reality'.

I hardly trust anyone who can not back up his/her statements in a reliable fashion (or has done so before, which gives some reputation). Look here for some really beautiful crap (unfortunately from ADD; sad example): http://www.bluelight.ru/vb/showthread.php?t=399757

_BACK ON TOPIC!

Murphy
 
nuke said:
Sounds like a recipe for disaster -- if you destroy the receptor binding sites you're basically administering a neurotoxin.
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Sure, but I'd say from the info known it's not any more more neurotoxic than the likes of amphetamine, which phosphorylate the receptor binding sites which make them have to be 'internalized': that is, destroyed by the body to create a new receptor life cycle. Essentially the same process.
 
Amphetamine is a poor dopamine receptor ligand. It does phosphorlyate the binding site on DAT. The internalization of a transporter protein is a pretty common occurence. Transporter proteins are not analogous to G-protein coupled receptors.

What I was referring to in regards to toxicity was stuff like axon ablation from acute doses of MDMA or MA. Of course, destruction of the receptor shouldn't be quite as dangerous, but you will be damaging your internal signalling system.

What is the half life for a GPCR?
 
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